Ophthalmic and contact lens wetting solutions

ABSTRACT

An ophthalmic solution comprising a polyethoxylated glyceride in the range of 0.001 to about 10 percent by weight and a buffer agent. These solutions impart surprising comfort and wearability to contact lenses. At the same time the solutions provide good preservative capacity and do not increase protein deposit.

BACKGROUND

The present invention relates to novel ophthalmic solutions that containa ethoxylated glyceride as an additive to improve the wettability and todecrease the degree of protein and polymeric preservative binding tocontact lens surfaces. These compositions may also comprise other agentsin contact lens and ophthalmic solutions such as buffers, tonicityagents, wetting agents, enzymes, hydrogen peroxide, demulcents,thickeners, sequestering agents (chelating agents), surface activeagents and preservative agents. The ethoxylated glycerides areparticularly useful in contact lens treatment solutions, contact lenswetting solutions, solutions used to store contact lenses and solutionsused to clean or rinse contact lenses. It has been found thatsurprisingly the addition of ethoxylated glycerides improve the comfortof lenses treated with such solution and that this increased comfort issurprisingly long-lasting in its effect. The ethoxylated glycerides maybe mono-, di- or triglycerides,

The solutions of the present invention are made by one of two methods.First the ethoxylated glyceride may be melted and added to an aqueoussolution which includes the other agents to be used in the desiredformulation, or the additional agents may be added prior to the additionof the melted ethoxylated glyceride. Second, the ethoxylated glyceridemay be dissolved in an alcohol base and this liquid mixture, added tothe aqueous base. Ethoxylated glycerides are commercially available fromnumerous commercial sourcesand include Polyoxyl 40 hydrogenated castoroil (Cremophor RH 40), polyoxyl 60 hydrogenated castor oil (Cremophor RH60), PEG-30 Castor Oil (Incrocas 30), PEG-35 Castor Oil (Cremophor EL,Incrocas 35), or PEG-40 Castor Oil (Cremophor EL, Incrocas), CremophorEL ®, Emulphor EL ®, glycerol polyethyleneglycol riciinoleate, gycerolpolyethyleneglycol oxystearate, polyethoxylated hydrogenated castor oil,or polyethoxylated vegetable oil. The ethoxylated glycerides useful inthe present invention may include surfactants sold as PEG-6Caprylic/Capric Glycerides PEG-8 Caprylic/Capric Glycerides; PEG-2Castor Oil; PEG-3 Castor Oil; PEG-4 Castor Oil; PEG-5 Castor Oil; PEG-8Castor Oil; PEG-9 Castor Oil; PEG-10 Castor Oil; PEG-11 Castor Oil;PEG-15 Castor Oil; PEG-20 Castor Oil; PEG-25 Castor Oil; PEG-30 CastorOil; PEG-33 Castor Oil; PEG-35 Castor Oil; PEG-36 Castor Oil; PEG-40Castor Oil; PEG-50 Castor Oil; PEG-54 Castor Oil; PEG-55 Castor Oil;PEG-60 Castor Oil; PEG-100 Castor Oil; PEG-200 Castor Oil; PEG-18 CastorOil Dioleate; PEG-60 Corn Glycerides; PEG-20 Evening PrimroseGlycerides; PEG-60 Evening Primrose Glycerides; PEG-7 Glyceryl Cocoate;PEG-30 Glyceryl Cocoate; PEG-78 Glyceryl Cocoate; PEG-80 GlycerylCocoate; PEG-12 Glyceryl Dioleate; PEG-15 Glyceryl Isostearate; PEG-20Glyceryl Isostearate; PEG-30 Glyceryl Isostearate; PEG-60 GlycerylIsostearate; PEG-12 Glyceryl Laurate; PEG-20 Glyceryl Laurate; PEG-23Glyceryl Laurate; PEG-30 Glyceryl Laurate; PEG-10 Glyceryl Oleate;PEG-15 Glyceryl Oleate; PEG-30 Glyceryl Oleate; PEG-20 GlycerylRicinoleate; PEG-5 Glyceryl Sesquioleate; PEG-5 Glyceryl Stearate;PEG-10 Glyceryl Stearate; PEG-25 Glyceryl Stearate; PEG-30 GlycerylStearate; PEG-120 Glyceryl Stearate; PEG-200 Glyceryl Stearate; PEG-28Glyceryl Tallowate; PEG-80 Glyceryl Tallowate; PEG-200 GlycerylTallowate; PEG-5 Glyceryl Triisostearate; PEG-5 Hydrogenated Castor Oil;PEG-7 Hydrogenated Castor Oil; PEG-16 Hydrogenated Castor Oil; PEG-20Hydrogenated Castor Oil; PEG-25 Hydrogenate Castor Oil; PEG-30Hydrogenate Castor Oil; PEG-35 Hydrogenate Castor Oil; PEG-40Hydrogenate Castor Oil; PEG-45 Hydrogenate Castor Oil; PEG-50Hydrogenate Castor Oil; PEG-54 Hydrogenate Castor Oil; PEG-55Hydrogenate Castor Oil; PEG-60 Hydrogenate Castor Oil; PEG-80Hydrogenate Castor Oil; PEG-100 Hydrogenate Castor Oil; PEG-200Hydrogenate Castor Oil; PEG-40 Hydrogenated Castor Oil PCA Isosterate;PEG-5 Hydrogenated Corn Glycerides; and PEG-8 Hydrogenated FishGlycerides; which are all available from known commercial sources

The solutions of the present invention may contain other additivesincluding but not limited to buffers, tonicity agents, demulcents,wetting agents, preservatives, sequestering agents (chelating agents),surface active agents, and enzymes.

Other aspects of the claimed solutions include adding to the solutionfrom 0.001 to 1 weight percent chelating agent (preferably disodiumEDTA) and/or additional microbicide, (preferably 0.00001 to 0.1 or0.0000 1 to 0.01) weight percent polyhexamethylene biquanide (PHMB0,N-alkyl-2-pyrrolidone, chlorhexidine, polyquatemium-1, hexetidine,bronopol, alexidine, low concentrations of hydrogen peroxide, andophthalmologically acceptable salts thereof

Ophthalmologically acceptable chelating agents useful in the presentinvention include amino carboxylic acid compounds or water-soluble saltsthereof, including ethylenediaminetetraacetic acid, nitrilotriaceticacid, diethylenetriamine pentaacetic acid,hydroxyethylethylenediaminetriacetic acid,1,2-diaminocyclohexanetetraacetic acid, ethylene glycol bis(beta-aminoethyl ether) in N, N, N′, N′ tetraacetic acid (EGTA),aminodiacetic acid and hydroxyethylamino diacetic acid. These acids canbe used in the form of their water soluble salts, particularly theiralkali metal salts. Especially preferred chelating agents are the di-,tri- and tetra-sodium salts of ethylenediaminetetraacetic acid (EDTA),most preferably disodium EDTA (Disodium Edetate).

Other chelating agents such as citrates and polyphosphates can also beused in the present invention. The citrates which can be used in thepresent invention include citric acid and its mono-, di-, andtri-alkaline metal salts. The polyphosphates which can be used includepyrophosphates, triphosphates, tetraphosphates, trimetaphosphates,tetrametaphosphates, as well as more highly condensed phosphates in theform of the neutral or acidic alkali metal salts such as the sodium andpotassium salts as well as the ammonium salt.

The pH of the solutions should be adjusted to be compatible with the eyeand the contact lens, such as between 6.0 to 8.0, preferably between 6.8to 7.8 or between 7.0 to 7.6. Significant deviations from neutral (pH7.3) will cause changes in the physical parameters (i.e. diameter) insome contact lenses. Low pH (pH less than 5.5) can cause burning andstinging of the eyes, while very low or very high pH (less than 3.0 orgreater than 10) can cause ocular damage.

The additional preservatives employed in the present invention areknown, such as polyhexamethylene biguanide, N-alkyl-2-pyrrolidone,chlorhexidine, polyhexamethylenebiguanide, alexidine, polyquatemium-1,hexetidine, bronopol and a very low concentration of hydrogen peroxide,e.g., 30 to 200 ppm.

The solutions of the invention are compatible with both rigid gaspermeable and hydrophilic contact lenses during storage, cleaning,wetting, soaking, rinsing and disinfection.

A typical aqueous solution of the present invention may containadditional ingredients which would not affect the basic and novelcharacteristics of the active ingredients described earlier, such astonicity agents, surfactants and viscosity inducing agents, which mayaid in either the lens cleaning or in providing lubrication to the eye.Suitable tonicity agents include sodium chloride, potassium chloride,glycerol or mixtures thereof The tonicity of the solution is typicallyadjusted to approximately 240-310 milliosmoles per kilogram solution(mOsm/kg) to render the solution compatible with ocular tissue and withhydrophilic contact lenses. In one embodiment, the solution contains0.01 to 0.5 weight percent sodium chloride.

Suitable viscosity inducing agents can include lecithin or the cellulosederivatives such as hydroxymethylcellulose, hydroxypropylcellulose andmethylcellulose in amounts similar to those for surfactants, above.

EXAMPLE 1

Hydrophilic contact lenses were placed flat onto glass slides and rinsedwith water to remove any debris. These slides were placed in a petridish and covered with a few drops of each of the test solutionspreviously prepared in either water, an aqueous isotonic sodium chloridesolution, or an aqueous phosphate buffered solution made isotonic withsodium chloride and adjusted to pH 7.3. Eachpetri plate was covered andplaced in a refrigerator overnight. The following day, the slides wereremoved and allowed to equilibrate to room temperature. The lenses wererinsed with water and the excess water was removed. One 5 uL drop ofmineral oil stained with Oil Red O was placed onto one lens for eachsolution. After ten minutes, the lenses were observed for the ability ofthe oil drop to spread. Solution Oil Water Additive MatrixDispersibility Dispersibility 1% polyoxyl 40 water 4 5 hydrogenatedcastor oil (Cremophor RH 40) 1% polyoxyl 40 buffer 5 5 hydrogenatedcastor oil water (Cremophor RH 40) 1% polyoxyl 40 sodium 2 5hydrogenated castor oil choride (Cremophor RH 40) water 1% polyoxyl 40buffer 3 5 hydrogenated castor oil sodium (Cremophor RH 40) chloridewater 1% Polysorbate 80 sodium 4 5 (Tween 80) choride water 1%Poloxamine 1107 sodium 2 5 (Tetronic 1107) choride water 1% Poloxamer407 sodium 2 5 (Pluronic F127) choride water 1% Polysorbate 80 buffer 35 (Tween 80) sodium chloride water 1% Poloxamine 1107 buffer 1 5(Tetronic 1107) sodium chloride water 1% Poloxamer 407 buffer 1 5(Pluronic F127) sodium chloride water Water water 1 5Key1 non-spreading drop2 poor spreading drop3 moderate spreading drop4 increased spreading drop5 thin spreading film

The results demonstrates that exposure of the contact lens to theethoxylated glyceride will generate a durable modified surface capableof allow the formation of a thin oil and aqueous film. Thischaracteristic mimics mucin and is essential for the proper tear layerformation of over the lens. A score of 3 or better is consideredacceptable. This experiment also illustrates the synergistic improvementwhen the ethoxylated glyceride is exposed in the presence of a buffer.The inability of the Poloxamer and Poloxamine to allow the oil film tospread across the lens demonstrates that not all surface active agentswill promote the spreading of a properly formed tear film over thecontact lens surface.

EXAMPLE 2 Example of Protein Deposition Inhibition

Contact lenses were soaked and heated in test solutions to which aradio-labeled lysozyme was present in a known amount for a period of 12hours at 37 degrees Celsius. The lenses were rinsed with distilled waterin order to remove residual solution. The lenses were then assayed forprotein deposition using a Beckman BioGamma 1 counter. Results werereported in ug/lens. Lens A Lens B Average ug/lens ug/lens ug/lensPhosphate buffer control 1,043 865 954 Cremophor RH40 (1%) 15 23 19 InPhosphate Buffer

Ethoxylated Castor Oil was a 1 percent w/v solution. The matrix controlwas phosphate buffer and sodium chloride. The polyoxyl 40 hydrogenatedcastor oil solution had lower protein binding than the control.

EXAMPLE 3 Example of Protein Deposition Inhibition

Isotonic aqueous phosphate buffered solutions were prepared and adjustedto pH 7.4. Contact lenses were soaked in 25 mL of the test solutionsovernight. Afterwards, lysozyme was added to the tubes and warmed to 37degrees Celsius for 12 hours. The lenses were rinsed with distilledwater in order to remove residual solution. The lenses were assayed forprotein deposition by the BCA method and detected on an HP PDASpectrophotometer. Results were reported in ug/lens. Solution uglysozyme per lens Marketed Product Control >18.3 (phosphate buffer,Poloxamer) Phosphate buffer control >26.16 Cremophor RH40 (1%) 9.78 InPhosphate Buffer

Ethoxylated Castor Oil was a 1 percent w/v solution. The matrix controlwas phosphate buffer and sodium chloride. The polyoxyl 40 hydrogenatedcastor oil solution had lower protein binding than the control.

EXAMPLE 4

An example of a preferred disinfecting formulation of the subjectinvention is provided below in Table I. This solution is prepared byweighing out the necessary amount of the tricine, creatine, cholinechloride, sodium chloride and edetate disodium into a vessel containingapproximately 90% of the water volume. After each of the ingredients hasdissolved, the pH is adjusted to 7.3 with either 1 N sodium hydroxide or1 N hydrochloric acid. Following this, the polyhexamethylene biguanideis added and the solution is brought to final volume with purifiedwater. The final product has the composition shown in the Table below.Constituent Weight/Volume Polyhexamethyl- 20% w/w solution 0.0001%enebiguanide HCl available under the mark Cosmocil CQ, from AveciaTricine Spectrum   1.0% Creatine Spectrum  0.25% Choline ChlorideAmersco   0.5% Edetate Disodium Spectrum  0.055% Polyoxyl 40 CremophorRH 40 from   0.1% Hydrogenated Castor BASF Co. Oil Sodium ChlorideFisher Scientific As required for tonicity adjustment 300 mOsmHydrochloride Acid, 1 N VWR as required for pH adjustment to 7.3 SodiumHydroxide, 1 N Mallinckrodt as required for pH adjustment to 7.3Purified Water Balance to 100%

This solution may be used to rinse, clean, and store contact lenses on adaily basis.

EXAMPLE 5

An example of a preferred formulation for a contact lens vial storage ofthe subject invention is provided below in Table I. This solution isprepared by weighing out the necessary amount of the sodium borate,boric acid, and sodium chloride into a vessel containing approximately90% of the water volume. After each of the ingredients has dissolved,the pH is adjusted to 7.3 with either 1 N sodium hydroxide or 1 Nhydrochloric acid. The final product had the composition shown in TableI below. Constituent Weight/Volume Sodium Borate Spectrum  1.0% BoricAcid Spectrum 0.25% Polyoxyl 40 Hydrogenated Cremophor RH40  0.1% CastorOil from BASF Co. Sodium Chloride Fisher Scientific As required fortonicity adjustment 300 mOsm Hydrochloride Acid, 1 N VWR as required forpH adjustment to 7.3 Sodium Hydroxide, 1 N Mallinckrodt as required forpH adjustment to 7.3 Purified Water Balance to 100%

EXAMPLE 6

The following are useful disinfecting solutions within the scope of thepresent invention that may be used for all purpose disinfectingsolutions. They are made according to generally acceptable proceduresexcept that the ethoxylated glycerides must be first be dissolved inwarm water prior to the addition of the other components. % Weight/Constituent Supplier Volume Amount Purified water to 80% 40 mL TricineSpectrum  1.0%  0.500 g Carnitine Spectrum  0.25%  0.125 g Betaine HClSpectrum  0.1%  0.050 g Choline Chloride Amresco  0.5%  0.250 g InositolSpectrum  0.1%  0.050 g Edetate Disodium Spectrum 0.055% 0.0275 gPolyoxyl 40 Hydrogenated Cremophor RH 40  0.1% 0.5 mL of 10% Castor Oilfrom BASF Co. Hydrochloride Acid, 1 N as required for pH as required forpH adjustment to 7.3 adjustment to 7.3 Sodium Hydroxide, 1 N as requiredfor pH as required for pH adjustment to 7.3 adjustment to 7.3 PurifiedWater to 98% Dilute to 49 mL Sodium Chloride Fisher As required for Asrequired for tonicity adjustment tonicity adjustment 300 mOsm 300 mOsmPolyhexamethylene- 20% w/w solution 0.0001% 50 uL of 0.1% biguanide HClavailable under the mark Cosmocil CQ from Avecia Purified Water Balanceto 100% Dilute to 50 mL

EXAMPLE 7

The following are formulations within the scope of the invention offormulations intended to be used as lens-vial solutions that are used tostore lenses prior to their use. These solutions have the effect oftreating the contact lens in the solution and rendering the lens morecomfortable in use. % Weight/ Constituent Supplier Volume AmountPurified water to 80% 40 mL Tricine Spectrum  1.0% 0.500 g CarnitineSpectrum 0.25% 0.125 g Inositol Spectrum  0.1% 0.050 g HydrochlorideAcid, 1 N as required for pH as required for pH adjustment to 7.3adjustment to 7.3 Sodium Hydroxide, 1 N as required for pH as requiredfor pH adjustment to 7.3 adjustment to 7.3 Polyoxyl 40 HydrogenatedCremophor RH 40  0.1% 0.5 mL of 10% Castor Oil from BASF Co. PurifiedWater to 98% Dilute to 49 mL Sodium Chloride Fisher As required for Asrequired for tonicity adjustment tonicity adjustment 300 mOsm 300 mOsmPurified Water to 100% Dilute to 50 mL

1. An ophthalmic contact lens solution comprising: 0.001 to 10 percentby weight ethoxylated glyceride; 0.001 to 2 weight percent of aphysiologically acceptable buffer adjusted so the pH of solution isbetween 6.5 and 7.8 and the balance water.
 2. An ophthalmic contact lenssolution comprising: 0.001 to 10 percent by weight ethoxylatedglyceride; 0.001to 2 weight percent of a physiologically acceptabletonicity agent adjusted so the solution is isotonic between 200 and 400mOsm
 3. An ophthalmic solution comprising; 0.001 to 10 percent by weightethoxylated glyceride; 0.00001 to 0.1 weight percent of a preservativeagent.
 4. The solution of claim 1 which further comprises 0.01 to 2weight percent of a physiologically acceptable tonicity agent adjustedso the solution is isotonic between 200 and 400 mOsm
 5. The solution ofclaim 4 that further comprises 0.00001 to 0.1 weight percent of apreservative.
 6. The solution of claim 1 wherein the ethoxylatedglyceride is chosen from the group of compounds consisting of Polyoxyl40 hydrogenated castor oil (Cremophor RH 40), polyoxyl 60 hydrogenatedcastor oil (Cremophor RH 60), PEG-30 Castor Oil (Incrocas 30), PEG-35Castor Oil (Cremophor EL, Incrocas 35), or PEG-40 Castor Oil (CremophorEL, Incrocas), Cremophor EL ®, Emulphor EL ®, glycerolpolyethyleneglycol riciinoleate, gycerol polyethyleneglycol oxystearate,polyethoxylated hydrogenated castor oil, or polyethoxylated vegetableoil.
 7. The solution of claim 1 wherein the buffer is selected from thegroup consisting of organic amines, organic carboxylic acids,amphoterics, phosphates, or borates.
 8. Method for rendering a contactlens wettable by contacting the surface of said lens with an aqueoussolution comprising from 0.001 to about 10 precent by weight of anethoxylated glyceride.
 9. The method of claim 8 wherein the theethoxylated glyceride is polyoxyl 40 hydrogenated castor oil.
 10. Themethod of claim 7 wherein said ethoxylated glyceride is polyoxyl 60hydrogenated castor oil.
 11. The method of claim 7 wherein saidethoxylated glyceride is polyoxyl 40 hydrogenated castor oil.
 12. Themethod of claim 7 wherein said ethoxylated glyceride is polyoxyl 35castor oil.
 13. The method of claim 7 wherein the aqueous solutionfurther comprises the bufferbis(2-hydroxyethyl)iminotris(hydroxymethyl)methane (Bis-Tris) and itssalts.
 14. The method of claim 7 wherein the aqueous solution furthercomprises the 1,2-bis[tris(hydroxymethyl)-methylamino}propane (Bis-TrisPropane) and its salts.
 15. The method of claim 7 wherein the aqueoussolution further comprises the N-tris(hydroxymethyl) methyl glycine(Tricine) and its salts.
 16. The method of claim 7 wherein the aqueoussolution further comprises the N,N-bis(2-hydroxyethyl)-glycine (Bicine)and its salts.
 17. The method of claim 7 wherein the aqueous solutionfurther comprises the betaine and its salts.
 18. The method of claim 7wherein the aqueous solution further comprises the buffer phosphate andits salts
 19. The method of claim 7 wherein the aqueous solution furthercomprises the buffer is borate and its salts
 20. The method of claim 7wherein the aqueous solution further comprises the is citrate and itssalts
 21. The method of claim 7 wherein the aqueous solution furthercomprises is TRIS and its salts
 22. The method of claim 7 wherein theaqueous solution further comprises the buffer is2-amino-2-methyl-1,3-propanediol and its salts
 23. The method of claim 7wherein the aqueous solution further comprises the buffer istriisopropanolamine and its salts
 24. The method of claim 7 wherein theaqueous solution further comprises the buffer is camitine and its salts25. The method of claim 7 wherein the aqueous solution further comprisesthe buffer is dimethyl glutamate and its salts
 26. The method of claim 7wherein the aqueous solution further comprises the buffer is creatineand its salts
 27. The method of claim 7 wherein the aqueous solutionfurther comprises the buffer is diethanolamine and its salts
 28. Themethod of claim 7 wherein the aqueous solution further comprises thebuffer is diisopropylamine and its salts
 29. The method of claim 7wherein the aqueous solution further comprises the buffer istriethanolamine and its salts
 30. The method of claim 7 wherein theaqueous solution further comprises the buffer is triethylamine and itssalts
 31. The method of claim 7 wherein the aqueous solution furthercomprises the buffer is dimethyl aspartic acid and its salts
 32. Themethod of claim 7 wherein the aqueous solution further comprises thebuffer is imidazole and its salts
 33. The method of claim 7 wherein theaqueous solution further comprises the buffer is histidine and its salts34. The method of claim 7 wherein the aqueous solution further comprisesthe buffer is methyl aspartate and its salts 35 The method of claim 7wherein the aqueous solution further comprises the buffer isTris(hydroxymethyl)aminomethane (Tromethamine, TRIS) and its salts
 35. Acontact lens product comprising: A contact lens: A sealable container;and An effective amount of an ophthalmic lens solution comprising: 0.001to 10 percent by weight ethoxylated glyceride; 0.01 to 2 weight percentof a physiologically acceptable buffer adjusted so the pH of solution isbetween 6.5 and 7.8 and the balance water.
 37. The method of claim 7wherein the buffer is glycine and its salts
 38. The method of claim 7wherein the buffer is lysine and its salts
 39. The method of claim 7wherein the buffer is histidine and its salts.